The causes of chronic kidney disease (CKD) are many but can be grouped into the three main areas of diabetes, glomerulonephritis (inflammation in the kidney) and a collection of single gene defects (polycystic kidney disease being the most common gene defect). Glomerulonephritis (GN) accounts for 25-30% of CKD and is often diagnosed when patients present with proteinuria and/or haematuria. If proteinuria is greater than 3.5 gm/24 hr, the patient may present with nephrotic syndrome which is associated with oedema, and increased risk of thromboembolism and cardiovascular disease. Classically, GN is diagnosed following renal biopsy and histopathological analysis of the glomerular pathology, where structural changes in the glomerulus revealed by light and electron microscopy in combination with immunostaining allow classification into types of glomerulonephritis. Incidences of GN vary across the world due to two major variables, firstly the frequency and use of renal biopsy and secondly the ethnic genetic background of the country/region. In adults, nephrotic syndrome is most commonly caused by membranous nephropathy (MN, 8-12 cases per million population), and focal segmental glomerulonephritis (FSGS, 2-5 cases per million population) Hanko J 2009, Mcquarrie 2010. In children, cases of nephrotic syndrome are estimated at 160 case per million children, with 80% caused by steroid sensitive nephrotic syndrome (minimal change disease) and 20% by steroid resistant nephrotic syndrome (FSGS) (Gbadegesin 2012). IgA nephropathy, commonly presenting in both adults and children with haematuria with or with proteinuria and hypertension is the commonest biopsy finding with mesangial deposits of IgA and complement C3.
While biopsy classification coupled with clinical presentation provides a framework for understanding each type of renal disease, there is often wide variation between patients in disease activity, severity, response to immunosuppression and clinical outcome. Biopsy may not truly reflect the disease process due to sampling errors and is just a snapshot that can't be repeated as a routine management tool on a frequent basis.
What is required is one or more biomarkers of each specific disease mechanism that act as true surrogates of the mechanism such that by monitoring these markers, clinical management information on the disease activity, severity, response to treatment and outcome is obtained. A recent example of what appears to be a good surrogate marker of the disease mechanism in idiopathic membranous nephropathy is the autoantibody anti-PLA2R (Beck et al 2009)
IQCJ was identified as a partner in a novel human fusion gene IQCJ-SCHIP1 in 2006 in the context of genetic investigations in an individual with a 3q25-q29 inversion and language delay. Exploration of IQCJ-SCHIP1 expression in studies on human tissue identified two transcripts predominantly in fetal and adult brain and incidentally in kidney. In cultured neuronal cells IQCJ-SCHIP1 interacts with calmodulin through the conserved IQ domain and has been shown to align to actin filaments in neurite extensions.
Some aspects of the invention include methods of treating a patient who has or is at risk of developing kidney disease.
Other aspects include medical uses of a binding partner for an anti-IQCJ antibody, and methods of preventing or treating kidney disease in a subject using such binding partners.
Still other aspects include devices for the extracorporeal treatment of a patient's blood.
In a first aspect, the invention provides a method of diagnosing kidney disease in a subject, the method comprising: assaying a sample of a body fluid for the presence of an anti-IQCJ antibody in the subject's body fluid, wherein the presence of an anti-IQCJ antibody in the sample indicates that the subject has kidney disease.
In a second aspect, the invention provides a method of selecting a suitable regimen for the prevention or treatment of kidney disease, the method comprising: assaying a sample of a body fluid for the presence of an anti-IQCJ antibody in the subject's body fluid, wherein the presence of an anti-IQCJ antibody in the sample indicates that the subject will benefit from a regimen for prevention or treatment of kidney disease utilising a binding partner for an anti-IQCJ antibody.
In a third aspect, the invention provides a method of monitoring effectiveness in a subject of a treatment regimen for prevention or treatment of kidney disease, the method comprising: assaying a sample of a body fluid of a subject undergoing a treatment regimen for prevention or treatment of kidney disease, to obtain a value representative of the amount of anti-IQCJ antibodies present in the subject's body fluid sample; comparing the value obtained with a reference value; and based on this comparison, determining whether the subject's treatment regimen is effective for prevention or treatment of kidney disease.
Methods of the first or second aspects of the invention may further comprise obtaining a value representative of the amount of anti-IQCJ antibodies present in the sample from the subject, and comparing this obtained value with a reference value. Examples of such embodiments are discussed further below.
As discussed further below, methods in accordance with the first, second, or third aspects of the invention may optionally further comprise a step of implementing a suitable regimen for the prevention or treatment of kidney disease. More details of these embodiments are provided elsewhere in the specification.
Alternatively or additionally, the methods of the first, second, or third aspects of invention may further comprise assessment of one or more additional markers indicative of kidney disease. Examples of such additional markers are considered elsewhere in the specification.
In a fourth aspect, the invention provides a binding partner for an anti-IQCJ antibody for use in the prevention or treatment of kidney disease.
In a fifth aspect, the invention provides a method of preventing or treating kidney disease in a subject, the method comprising: contacting a volume of the subject's blood with a binding partner for an anti-IQCJ antibody, such that anti-IQCJ antibodies present in the subject's blood are able to bind to and be retained by the binding partner; and separating the binding partner and bound anti-IQCJ antibody from the blood, to yield an antibody-depleted volume of blood.
In a sixth aspect, the invention provides a device for extracorporeal treatment of a patient's blood, the device comprising: a binding partner for an anti-IQCJ antibody; and means for separating the binding partner from blood.
A first embodiment of the invention includes a method of treating a patient, said method comprising the steps of: contacting a binding partner for an anti-IQCJ antibody with a portion of a body fluid, wherein the fluid is from a patient; and determining the presence of an anti-IQCJ antibody in the subject's body fluid using a technique selected from the group consisting of: enzyme linked immunosorbent assays (ELISAs), western blotting, fluorescent bead-based immunoassays, and immunofluorescence on cell expressed IQCJ.
A second embodiment of the invention includes the method according to the first embodiment, further comprising the step of: treating the patient for kidney disease.
A third embodiment of the invention includes the method according to the first embodiment, further comprising the steps of: obtaining a value representative of the amount of anti-IQCJ antibodies in the patient's bodily fluid; and comparing the obtained value with a reference value.
A fourth embodiment of the invention includes the method according to the first embodiment, further comprising the step of: determining the presence of at least one marker selected from the group consisting of: anti-PLA2R antibodies; anti-nephrin antibodies; and anti-podocin antibodies in the patient's bodily fluid.
A fifth embodiment of the invention includes the method according to the second embodiment, wherein the patient is treated for at least one kidney disease selected from the group consisting of: primary renal failure, membranous nephropathy, de novo membranous nephropathy, IQCJ podocytopathy, and focal segmental glomerulosclerosis.
A sixth embodiment of the invention includes the method according to the first embodiment, wherein the bodily fluid is selected from the group consisting of: blood, serum, plasma, urine, and interstitial fluid.
A seventh embodiment of the invention includes the method according to the first embodiment, wherein said binding partner comprises an epitope recoginzed by the anti-IQCJ antibodies.
An eighth embodiment of the invention includes the method according to the seventh embodiment, wherein said binding partner includes at least one compound selected from the group consisting of: a compound that has 70% identity with SEQ ID NO:1 and a compound that has 100% identity with SEQ ID NO:1.
A ninth embodiment of the invention includes the method according to the seventh embodiment, wherein said binding partner further comprises a retention moiety selected from the group consisting of: a magnetic bead and a substrate.
A tenth embodiment of the invention includes a device for extracorporeal treatment of a patient's blood, the device comprising: a binding partner for an anti-IQCJ antibody; and an insoluble structure, wherein said binding partner comprises an epitope recognized by the anti-IQCJ antibodies, and wherein the insoluble structure is attached to the binding partner.
An eleventh embodiment of the invention includes the device according to the tenth embodiment, wherein the insoluble structure includes at least one material is selected from the group consisting of: cellulose, cellulose derivatives, agarose, agarose derivatives, polysulphone, polysulphone derivatives, polyacrylamide, polyacrylamide derivatives, and nylon.
A twelfth embodiment of the invention includes the device according to the eleventh embodiment, wherein the insoluble structure is selected from the group consisting of: hollow fibre cassettes, membranes, and beads.
A thirteenth embodiment of the invention includes a method of preventing or treating kidney disease comprising the steps of: contacting a portion of a patient's blood with an anti-IQCJ antibody; retaining the binding partner that is bound to the anti-IQCJ antibody in the portion of the patient's blood; and separating the binding partner and the bound anti-IQCJ antibody from the blood of the patient.
A fourteenth embodiment of the invention includes the method according to the thirteenth embodiment, wherein said binding partner includes at least one compound selected from the group consisting of: a compound that has 70% identity with SEQ ID NO:1 and a compound that has 100% identity with SEQ ID NO:1.
A fifteenth embodiment of the invention includes the method according to the fourteenth embodiment, wherein said binding partner further comprises a retention moiety selected from the group consisting of: a magnetic bead and a substrate.
A sixteenth embodiment of the invention includes the method according to the thirteenth embodiment, wherein the contacting step, the retaining step, and the separating step are performed extracorporeally.
A seventeenth embodiment of the invention includes the method according to the sixteenth embodiment, further comprising the step of: providing the antibody-depleted blood back to the patient.
An eighteenth embodiment of the invention includes the method according to the sixteenth embodiment, wherein the binding partner is provided in an arrangement so that the patient's blood may flow over the binding partner, thus allowing it to bind anti-IQCJ antibodies in the blood.
A nineteenth embodiment of the invention includes the method according to the thirteenth embodiment, wherein the patient has or is at risk of developing at least one kidney disease selected from the group consisting of: primary renal failure, membranous nephropathy, de novo membranous nephropathy, IQCJ podocytopathy, and focal segmental glomerulosclerosis.
A twentieth embodiment of the invention includes the method according to the thirteenth embodiment, wherein the contacting step, the retaining step, and the separating step are carried out “in line.”